New data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis

Author(s)
Lee, Sang Hong
Byrne, Enda M
Karlsson, Robert
Mattheisen, Manuel
Mattingsdal, Morten
McCarroll, Steven A
Medeiros, Helena
Melle, Ingrid
Milanova, Vihra
Myin-Germeys, Inez
Neale, Benjamin M
Ophoff, Roel A
Owen, Michael J
Mantzioris, Vasilis X
Pimm, Jonathan
Purcell, Shaun M
Puri, Vinay
Quested, Digby J
Rossin, Lizzy
Ruderfer, Douglas
Sanders, Alan R
Shi, Jianxin
Sklar, Pamela
St Clair, David
McGrath, John J
Stroup, T Scott
Van Os, Jim
Visscher, Peter M
Wiersma, Durk
Zammit, Stanley
Bridges, S Louis
Choi, Hyon K
Coenen, Marieke J H
de Vries, Niek
Dieude, Philippe
Mehta, Divya
Greenberg, Jeffrey D
Huizinga, Tom W J
Padyukov, Leonid
Siminovitch, Katherine A
Tak, Paul P
Worthington, Jane
De Jager, Philip L
Denny, Joshua C
Gregersen, Peter K
Klareskog, Lars
Stahl, Eli A
Mariette, Xavier
Plenge, Robert M
van Laar, Mart
van Riel, Piet
Zhao, Qiongyi
Kendler, Kenneth S
Sullivan, Patrick F
Price, Alkes L
O’Donovan, Michael
Hultman, Christina M
Okada, Yukinori
Mowry, Bryan J
Raychaudhuri, Soumya
Wray, Naomi R
Byerley, William
Cahn, Wiepke
Cantor, Rita M
Cichon, Sven
Cormican, Paul
Curtis, David
Kahler, Anna
Djurovic, Srdjan
Escott-Price, Valentina
Gejman, Pablo V
Georgieva, Lyudmila
Giegling, Ina
Hansen, Thomas F
Ingason, Andres
Kim, Yunjung
Konte, Bettina
Lee, Phil H
Vinkhuyzen, Anna A E
McIntosh, Andrew
McQuillin, Andrew
Morris, Derek W
Nothen, Markus M
O'Dushlaine, Colm
Olincy, Ann
Olsen, Line
Pato, Carlos N
Pato, Michele T
Pickard, Benjamin S
Ripke, Stephan
Posthuma, Danielle
Rasmussen, Henrik B
Rietschel, Marcella
Rujescu, Dan
Schulze, Thomas G
Silverman, Jeremy M
Thirumalai, Srinivasa
Werge, Thomas
Agartz, Ingrid
Amin, Farooq
Andreassen, Ole A
Azevedo, Maria H
Bass, Nicholas
Black, Donald W
Blackwood, Douglas H R
Bruggeman, Richard
Buccola, Nancy G
Choudhury, Khalid
Cloninger, C Robert
Corvin, Aiden
Craddock, Nicholas
Frisell, Thomas
Daly, Mark J
Datta, Susmita
Donohoe, Gary J
Duan, Jubao
Dudbridge, Frank
Fanous, Ayman
Freedman, Robert
Freimer, Nelson B
Friedl, Marion
Gill, Michael
Gusev, Alexander
Gurling, Hugh
De Haan, Lieuwe
Hamshere, Marian L
Hartmann, Annette M
Holmans, Peter A
Kahn, Rene S
Keller, Matthew C
Kenny, Elaine
Kirov, George K
Krabbendam, Lydia
Hu, Xinli
Krasucki, Robert
Lawrence, Jacob
Lencz, Todd
Levinson, Douglas F
Lieberman, Jeffrey A
Lin, Dan-Yu
Linszen, Don H
Magnusson, Patrik K E
Maier, Wolfgang
Malhotra, Anil K
Publication Date
2015
Abstract
Background: A long-standing epidemiological puzzle is the reduced rate of rheumatoid arthritis (RA) in those with schizophrenia (SZ) and vice versa. Traditional epidemiological approaches to determine if this negative association is underpinned by genetic factors would test for reduced rates of one disorder in relatives of the other, but sufficiently powered data sets are difficult to achieve. The genomics era presents an alternative paradigm for investigating the genetic relationship between two uncommon disorders. Methods: We use genome-wide common single nucleotide polymorphism (SNP) data from independently collected SZ and RA case-control cohorts to estimate the SNP correlation between the disorders. We test a genotype X environment (GxE) hypothesis for SZ with environment defined as winter- vs summer-born. Results: We estimate a small but significant negative SNP-genetic correlation between SZ and RA (−0.046, s.e. 0.026, P =0.036). The negative correlation was stronger for the SNP set attributed to coding or regulatory regions (−0.174, s.e. 0.071, P =0.0075). Our analyses led us to hypothesize a gene-environment interaction for SZ in the form of immune challenge. We used month of birth as a proxy for environmental immune challenge and estimated the genetic correlation between winter-born and non-winter born SZ to be significantly less than 1 for coding/regulatory region SNPs (0.56, s.e. 0.14, P =0.00090). Conclusions: Our results are consistent with epidemiological observations of a negative relationship between SZ and RA reflecting, at least in part, genetic factors. Results of the month of birth analysis are consistent with pleiotropic effects of genetic variants dependent on environmental context.
Citation
International Journal of Epidemiology, 44(5), p. 1706-1721
ISSN
1464-3685
0300-5771
Link
Publisher
Oxford University Press
Title
New data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis
Type of document
Journal Article
Entity Type
Publication

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